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Abrogation of the Brd4-positive transcription elongation factor B complex by papillomavirus E2 protein contributes to viral oncogene repression.

Abstract
The cellular bromodomain protein Brd4 is a major interacting partner of the papillomavirus (PV) E2 protein. Interaction of E2 with Brd4 contributes to viral episome maintenance. The E2-Brd4 interaction also plays an important role in repressing viral oncogene expression from the integrated viral genome in human PV (HPV)-positive cancer cells. However, the underlying mechanism is not clearly understood. In host cells, Brd4 recruits positive transcription elongation factor b (P-TEFb) to stimulate RNA polymerase II phosphorylation during cellular and viral gene expression. P-TEFb associates with the C terminus of Brd4, which largely overlaps with the E2 binding site on Brd4. In this study, we demonstrate that E2 binding to Brd4 inhibits the interaction of endogenous Brd4 and P-TEFb. P-TEFb is essential for viral oncogene E6/E7 transcription in both HeLa and CaSki cells that contain integrated HPV genomes. E2 binding to Brd4 abrogates the recruitment of P-TEFb to the integrated viral chromatin template, leading to inactivation of P-TEFb and repression of the viral oncogene E6/E7. Furthermore, dissociation of the Brd4-P-TEFb complex from the integrated viral chromatin template using a Brd4 bromodomain dominant-negative inhibitor also hampers HPV E6/E7 oncogene expression. Our data support that Brd4 recruitment of P-TEFb to the viral chromatin template is essential for viral oncogene expression. Abrogation of the interaction between P-TEFb and Brd4 thus provides a mechanism for E2-mediated repression of the viral oncogenes from the integrated viral genomes in cancer cells.
AuthorsJunpeng Yan, Qing Li, Sam Lievens, Jan Tavernier, Jianxin You
JournalJournal of virology (J Virol) Vol. 84 Issue 1 Pg. 76-87 (Jan 2010) ISSN: 1098-5514 [Electronic] United States
PMID19846528 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • BRD4 protein, human
  • DNA-Binding Proteins
  • E2 protein, Human papillomavirus type 16
  • E6 protein, Human papillomavirus type 16
  • Nuclear Proteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • Transcription Factors
  • oncogene protein E7, Human papillomavirus type 16
  • Positive Transcriptional Elongation Factor B
Topics
  • Alphapapillomavirus (genetics)
  • Cell Line
  • Cell Line, Tumor
  • DNA-Binding Proteins (physiology)
  • Genes, Viral
  • Humans
  • Nuclear Proteins (metabolism)
  • Oncogene Proteins, Viral (antagonists & inhibitors, genetics, physiology)
  • Papillomaviridae (chemistry, physiology)
  • Papillomavirus E7 Proteins
  • Positive Transcriptional Elongation Factor B (antagonists & inhibitors, genetics, metabolism)
  • Promoter Regions, Genetic
  • Protein Binding
  • Repressor Proteins (antagonists & inhibitors, genetics)
  • Transcription Factors (metabolism)
  • Transcription, Genetic

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